Nicholas J. Vogelzang, MD, FASCO, FACP: I think what you’re sort of hinting at, Dan, is that in the TKI world, it’s pretty clear when to move on. What do you move on to? Let’s say you use pazopanib as your first-line therapy, it’s pretty clear that if you have no symptomatic rapid disease progression, you’ll probably go to nivolumab. On the other hand, if you have symptomatic progression with liver metastases, I use cabozantinib. I’m going to say, “Wow, that’s a metastatic progression, and I want to get that drug in there right away.” The bigger question is if you’ve chosen to use nivolumab, and then you get this immunologic cloud around the tumor, and you’re thinking, “Hmm, I don’t know what that means.” You convey that to the patient, and the patient looks at you and says, “Do you really know what you’re doing? How long you been doing this, Doctor?” I’ve got enough gray hair to be able to say I’ve been doing this a long time, but I haven’t been doing nivolumab for that long of a time, so you don’t know. The uncertainty is what drives a lot of patients a little bit bonkers—when you’re using second-line nivolumab and they’re already a little bit on edge, and you’re thinking, “I hope this is the right choice.”

Robert Alter, MD: I actually discuss with them how the CheckMate-025 clinical trial was. You’ve got 4 doses of nivolumab. If you had that pseudoprogression and patients were still having no clinical progression symptomatically, you were allowed to give 2 more doses and then rescan the tumor. In my practice, I give not 4 doses but 6 doses of nivolumab. I give it a little bit more time. If I’m having that pseudoprogression concern and they’re still not having any symptomatic progression, I would definitely go 2 or 3 more doses and push a little bit more. I still think you have to really take care of the patient. If they’re symptomatically OK with it, it’s a conversation. I do not have many gray hairs left, but the patient has to be educated in the way we have become educated. I think they have to have that trust that we have, to let them feel that it’s evidence-based trust.

Bradley McGregor, MD: I think one of the things that’s really different about immunotherapy to me, compared with the TKIs regarding this concern of not giving up too soon, is that you really do get that tail to the curve when you look at the I-O therapies. We have the follow-up data from CheckMate-025, and there clearly seem to be those patients who have a really durable response to I-O therapy.

Daniel George, MD: What’s interesting is that they’re not all PRs or CRs. Some of that is stable disease. You can’t necessarily say, “Well, I didn’t get a dramatic result, so I’m not going to have a tail.” You get some of these patients that do. It’s difficult. We don’t want to give up on this stuff, but I think Nick is right. Generally speaking, we’re going to know when a patient is starting to get into trouble. When you see those symptoms and that deterioration, that’s when you know you need to change your approach.

Neeraj Agarwal, MD: Absolutely. How patients are doing is so important, so much more important than the scan results, right?

Daniel George, MD: That’s right. When there’s discordance, you go with how the patient looks, right?

Neeraj Agarwal, MD: Yes.

Daniel George, MD: I think that that’s the key thing in medicine—keeping that big picture because there’s so much more that we’re not measuring than we are measuring. The scans are just 1 point in time.

Robert Alter, MD: If they’re not having symptoms, obviously use the most mileage you get per therapy. Unfortunately, their survival is a sequence of many therapies until intolerance, symptoms, or death. If you can push a therapy longer or not discontinue it just because of angst, then I think we probably do best by patients in just letting them stay on therapy as long as they’re not having any symptoms to it.

Daniel George, MD: Now, what about side effects, Brad? We’re dealing with patients who have, in the frontline setting, some adverse events early on. We have 10 treatment options for these patients. It’s tempting to say, “Well, let’s just move on to treatment B because we have half the alphabet to get through here.” Is that the right thing to do? How do you counsel patients? How do you talk with your colleagues about managing AEs versus changing therapy?

Bradley McGregor, MD: There’s no guarantee that therapy B is going to be any better than therapy A. Obviously, if you’re on a therapy and especially if you’re getting clinical benefit from that therapy, you don’t want to abandon that therapy because you don’t know if that’s going to work or not. When you look at all the clinical studies done with every single TKI or any type of I-O therapy, patients get dose reductions and dose adjustments to find the right dosing. I know we do that all the time with dosing different schedules, like going to the sunitinib 2/1 schedule. Even with cabozantinib going to 40 mg daily, maybe they don’t tolerate the 40 mg, so you use 2 weeks on, 1 week off. You just try that dosing that gives the patient the best quality of life for as long as possible. I think for toxicities, there obviously comes a point where it’s unbearable and you have to switch. But really try to work with the dosing and the drugs that you have to try to find a dose that can work for that patient to give them the longest response possible.

Nicholas J. Vogelzang, MD, FASCO, FACP: It reminds me of a story. I had this fellow who was going to go to Rome. He’s got a little olive orchard outside of Rome, and he said, “Well, I’ll see you in 6 months.” He’s got neck nodes and mediastinal disease, and I’m thinking, “Six months? What are you thinking here?”

Daniel George, MD: He’s in denial.

Nicholas J. Vogelzang, MD, FASCO, FACP: No, he’s not. In this case, he was on fourth-line therapy and he’d had a great response to lenvatinib. He said, “Just give me some of that lenvatinib, and I’ll take it with me.” The guy comes back 6 months later happy as a clam, and all of his lumps are gone. He said, “Well, I would just take the drug whenever my lymph nodes got bigger, and they would shrink again.” And so you say, “OK, I guess you’ve figured it out.” Everyone does have their own dose adjustments, and we’re not always able to figure that out right away.

Daniel George, MD: I think that’s a great example. We have these cases of these patients who just seem to respond to one therapy after another. Nothing is curative, right? But we switch therapies, and we still get this disease control where we’re on 4, 5, 6, or 8 lines of therapy. Again, we don’t have to get through everything, but it’s nice to know that for these patients, we have a lot of lines of therapy. There’s a real comfort in being able to do that. I think getting into this second-line space now, we should not give up too early in the frontline space unless we’re seeing really unfavorable initial signs, and we see that we have to move on. When we don’t, we really want to try to maximize this as long as possible.

Transcript Edited for Clarity

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Transcript:

Nicholas J. Vogelzang, MD, FASCO, FACP: I think what you’re sort of hinting at, Dan, is that in the TKI world, it’s pretty clear when to move on. What do you move on to? Let’s say you use pazopanib as your first-line therapy, it’s pretty clear that if you have no symptomatic rapid disease progression, you’ll probably go to nivolumab. On the other hand, if you have symptomatic progression with liver metastases, I use cabozantinib. I’m going to say, “Wow, that’s a metastatic progression, and I want to get that drug in there right away.” The bigger question is if you’ve chosen to use nivolumab, and then you get this immunologic cloud around the tumor, and you’re thinking, “Hmm, I don’t know what that means.” You convey that to the patient, and the patient looks at you and says, “Do you really know what you’re doing? How long you been doing this, Doctor?” I’ve got enough gray hair to be able to say I’ve been doing this a long time, but I haven’t been doing nivolumab for that long of a time, so you don’t know. The uncertainty is what drives a lot of patients a little bit bonkers—when you’re using second-line nivolumab and they’re already a little bit on edge, and you’re thinking, “I hope this is the right choice.”

Robert Alter, MD: I actually discuss with them how the CheckMate-025 clinical trial was. You’ve got 4 doses of nivolumab. If you had that pseudoprogression and patients were still having no clinical progression symptomatically, you were allowed to give 2 more doses and then rescan the tumor. In my practice, I give not 4 doses but 6 doses of nivolumab. I give it a little bit more time. If I’m having that pseudoprogression concern and they’re still not having any symptomatic progression, I would definitely go 2 or 3 more doses and push a little bit more. I still think you have to really take care of the patient. If they’re symptomatically OK with it, it’s a conversation. I do not have many gray hairs left, but the patient has to be educated in the way we have become educated. I think they have to have that trust that we have, to let them feel that it’s evidence-based trust.

Bradley McGregor, MD: I think one of the things that’s really different about immunotherapy to me, compared with the TKIs regarding this concern of not giving up too soon, is that you really do get that tail to the curve when you look at the I-O therapies. We have the follow-up data from CheckMate-025, and there clearly seem to be those patients who have a really durable response to I-O therapy.

Daniel George, MD: What’s interesting is that they’re not all PRs or CRs. Some of that is stable disease. You can’t necessarily say, “Well, I didn’t get a dramatic result, so I’m not going to have a tail.” You get some of these patients that do. It’s difficult. We don’t want to give up on this stuff, but I think Nick is right. Generally speaking, we’re going to know when a patient is starting to get into trouble. When you see those symptoms and that deterioration, that’s when you know you need to change your approach.

Neeraj Agarwal, MD: Absolutely. How patients are doing is so important, so much more important than the scan results, right?

Daniel George, MD: That’s right. When there’s discordance, you go with how the patient looks, right?

Neeraj Agarwal, MD: Yes.

Daniel George, MD: I think that that’s the key thing in medicine—keeping that big picture because there’s so much more that we’re not measuring than we are measuring. The scans are just 1 point in time.

Robert Alter, MD: If they’re not having symptoms, obviously use the most mileage you get per therapy. Unfortunately, their survival is a sequence of many therapies until intolerance, symptoms, or death. If you can push a therapy longer or not discontinue it just because of angst, then I think we probably do best by patients in just letting them stay on therapy as long as they’re not having any symptoms to it.

Daniel George, MD: Now, what about side effects, Brad? We’re dealing with patients who have, in the frontline setting, some adverse events early on. We have 10 treatment options for these patients. It’s tempting to say, “Well, let’s just move on to treatment B because we have half the alphabet to get through here.” Is that the right thing to do? How do you counsel patients? How do you talk with your colleagues about managing AEs versus changing therapy?

Bradley McGregor, MD: There’s no guarantee that therapy B is going to be any better than therapy A. Obviously, if you’re on a therapy and especially if you’re getting clinical benefit from that therapy, you don’t want to abandon that therapy because you don’t know if that’s going to work or not. When you look at all the clinical studies done with every single TKI or any type of I-O therapy, patients get dose reductions and dose adjustments to find the right dosing. I know we do that all the time with dosing different schedules, like going to the sunitinib 2/1 schedule. Even with cabozantinib going to 40 mg daily, maybe they don’t tolerate the 40 mg, so you use 2 weeks on, 1 week off. You just try that dosing that gives the patient the best quality of life for as long as possible. I think for toxicities, there obviously comes a point where it’s unbearable and you have to switch. But really try to work with the dosing and the drugs that you have to try to find a dose that can work for that patient to give them the longest response possible.

Nicholas J. Vogelzang, MD, FASCO, FACP: It reminds me of a story. I had this fellow who was going to go to Rome. He’s got a little olive orchard outside of Rome, and he said, “Well, I’ll see you in 6 months.” He’s got neck nodes and mediastinal disease, and I’m thinking, “Six months? What are you thinking here?”

Daniel George, MD: He’s in denial.

Nicholas J. Vogelzang, MD, FASCO, FACP: No, he’s not. In this case, he was on fourth-line therapy and he’d had a great response to lenvatinib. He said, “Just give me some of that lenvatinib, and I’ll take it with me.” The guy comes back 6 months later happy as a clam, and all of his lumps are gone. He said, “Well, I would just take the drug whenever my lymph nodes got bigger, and they would shrink again.” And so you say, “OK, I guess you’ve figured it out.” Everyone does have their own dose adjustments, and we’re not always able to figure that out right away.

Daniel George, MD: I think that’s a great example. We have these cases of these patients who just seem to respond to one therapy after another. Nothing is curative, right? But we switch therapies, and we still get this disease control where we’re on 4, 5, 6, or 8 lines of therapy. Again, we don’t have to get through everything, but it’s nice to know that for these patients, we have a lot of lines of therapy. There’s a real comfort in being able to do that. I think getting into this second-line space now, we should not give up too early in the frontline space unless we’re seeing really unfavorable initial signs, and we see that we have to move on. When we don’t, we really want to try to maximize this as long as possible.